Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled, phase 3 study
Howard JF., Bresch S., Genge A., Hewamadduma C., Hinton J., Hussain Y., Juntas-Morales R., Kaminski HJ., Maniaol A., Mantegazza R., Masuda M., Sivakumar K., Śmiłowski M., Utsugisawa K., Vu T., Weiss MD., Zajda M., Boroojerdi B., Brock M., de la Borderie G., Duda PW., Lowcock R., Vanderkelen M., Leite MI., Sembinelli D., Teitelbaum J., Nicolle M., Bernard E., Svahn J., Spinazzi M., Stojkovic T., Demeret S., Weiss N., Le Guennec L., Messai S., Tranchant C., Nadaj-Pakleza A., Chanson JB., Suliman M., Zaidi L., Tard C., Lecointe P., Zschüntzsch J., Schmidt J., Glaubitz S., Zeng R., Scholl M., Kowarik M., Ziemann U., Krumbholz M., Martin P., Ruschil C., Dünschede J., Kemmner R., Rumpel N., Berger B., Totzeck A., Hagenacker T., Stolte B., Iorio R., Evoli A., Falso S., Antozzi C., Frangiamore R., Vanoli F., Rinaldi E., Deguchi K., Minami N., Nagane Y., Suzuki Y., Ishida S., Suzuki S., Nakahara J., Nagaoka A., Yoshimura S., Konno S., Tsuya Y., Uzawa A., Kubota T., Takahashi M., Okuno T., Murai H., Gilhus NE., Boldingh M., Rønning TH., Chyrchel-Paszkiewicz U., Kumor K., Zielinski T., Banaszkiewicz K., Błaż M., Kłósek A., Świderek-Matysiak M., Szczudlik A., Paśko A., Szczechowski L., Banach M., Ilkowski J., Kapetanovic Garcia S., Ortiz Bagan P., Belén Cánovas Segura A.
Background: Generalised myasthenia gravis is a chronic, unpredictable, and debilitating rare disease, often accompanied by high treatment burden and with an unmet need for more efficacious and well tolerated treatments. Zilucoplan is a subcutaneous, self-administered macrocyclic peptide complement C5 inhibitor. We aimed to assess safety, efficacy, and tolerability of zilucoplan in patients with acetylcholine receptor autoantibody (AChR)-positive generalised myasthenia gravis. Methods: RAISE was a randomised, double-blind, placebo-controlled, phase 3 trial that was done at 75 sites in Europe, Japan, and North America. We enrolled patients (aged 18–74 years) with AChR-positive generalised myasthenia gravis (Myasthenia Gravis Foundation of America disease class II–IV), a myasthenia gravis activities of daily living (MG-ADL) score of least 6, and a quantitative myasthenia gravis score of at least 12. Participants were randomly assigned (1:1) to receive subcutaneous zilucoplan 0·3 mg/kg once daily by self-injection, or matched placebo, for 12 weeks. The primary efficacy endpoint was change from baseline to week 12 in MG-ADL score in the modified intention-to-treat population (all randomly assigned patients who received at least one dose of study drug and had at least one post-dosing MG-ADL score). Safety was mainly assessed by the incidence of treatment-emergent adverse events (TEAEs) in all patients who had received at least one dose of zilucoplan or placebo. This trial is registered at ClinicalTrials.gov, NCT04115293. An open-label extension study is ongoing (NCT04225871). Findings: Between Sept 17, 2019, and Sept 10, 2021, 239 patients were screened for the study, of whom 174 (73%) were eligible. 86 (49%) patients were randomly assigned to zilucoplan 0·3 mg/kg and 88 (51%) were assigned to placebo. Patients assigned to zilucoplan showed a greater reduction in MG-ADL score from baseline to week 12, compared with those assigned to placebo (least squares mean change −4·39 [95% CI –5·28 to –3·50] vs −2·30 [–3·17 to –1·43]; least squares mean difference −2·09 [−3·24 to −0·95]; p=0·0004). TEAEs occurred in 66 (77%) patients in the zilucoplan group and in 62 (70%) patients in the placebo group. The most common TEAE was injection-site bruising (n=14 [16%] in the zilucoplan group and n=8 [9%] in the placebo group). Incidences of serious TEAEs and serious infections were similar in both groups. One patient died in each group; neither death (COVID-19 [zilucoplan] and cerebral haemorrhage [placebo]) was considered related to the study drug. Interpretation: Zilucoplan treatment showed rapid and clinically meaningful improvements in myasthenia gravis-specific efficacy outcomes, had a favourable safety profile, and was well tolerated, with no major safety findings. Zilucoplan is a new potential treatment option for a broad population of patients with AChR-positive generalised myasthenia gravis. The long-term safety and efficacy of zilucoplan is being assessed in an ongoing open-label extension study. Funding: UCB Pharma.